Pharmaceutical compositions comprising 17alpha-furanylesters of 17beta-carbothiate androstanes with a muscarinic receptor antagonist

ABSTRACT

A pharmaceutical composition comprising a compound of formula (I),  
                 
or a solvate thereof, in combination with a muscarinic receptor antagonist.

The present invention relates inter alia to pharmaceutical compositionscontaining a novel anti-inflammatory and an anti-allergic compound ofthe androstane series and to processes for their preparation. Thepresent invention also relates to therapeutic uses thereof, particularlyfor the treatment of inflammatory and allergic conditions.

Glucocorticoids which have anti-inflammatory properties are known andare widely used for the treatment of inflammatory disorders or diseasessuch as asthma, chronic obstructive pulmonary disease (COPD) andrhinitis. For example, U.S. Pat. No. 4,335,121 discloses 6α,9α-Difluoro-17α-(1-oxopropoxy)-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester (known by the generic name of fluticasonepropionate) and derivatives thereof. The use of glucocorticoidsgenerally, and especially in children, has been limited in some quartersby concerns over potential side effects. The side effects that arefeared with glucocorticoids include suppression of theHypothalamic-Pituitary-Adrenal (HPA) axis, effects on bone growth inchildren and on bone density in the elderly, ocular complications(cataract formation and glaucoma) and skin atrophy. Certainglucocorticoid compounds also have complex paths of metabolism whereinthe production of active metabolites may make the pharmacodynamics andpharmacokinetics of such compounds difficult to understand. Whilst themodern steroids are very much safer than those originally introduced, itremains an object of research to produce new molecules which haveexcellent anti-inflammatory properties, with predictable pharmacokineticand pharmacodynamic properties, with an attractive side effect profile,and with a convenient treatment regime.

Muscarinic receptor antagonists, especially those which are selectivefor M1 and/or M3 receptors over M2 receptors, have also found use inrelief of inflammatory disorders of the lung, especially COPD andasthma. Muscarinic receptor antagonists may desirably be employed intherapy in combination with glucocorticoid compounds for the treatmentof the aforementioned conditions.

We have now identified a novel composition comprising a novelglucocorticoid compound which substantially meets these objectives.

Thus, according to one aspect of the invention, there is provided apharmaceutical composition comprising compound of formula (I)

or a solvate thereof;in combination with a muscarinic receptor antagonist (hereinafter a“composition of the invention”).

The chemical name of the compound of formula (I) is 6α,9α-Difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester.

References hereinafter to the compound according to the inventioninclude both the compound of formula (I) and solvates thereof,particularly pharmaceutically acceptable solvates.

The compound of formula (I) and compositions containing it havepotentially beneficial anti-inflammatory or anti-allergic effects,particularly upon topical administration, demonstrated by, for example,its ability to bind to the glucocorticoid receptor and to illicit aresponse via that receptor, with long acting effect. Hence, the compoundof formula (I) is useful in the treatment of inflammatory and/orallergic disorders, especially in once-per-day therapy.

Preferably the muscarinic receptor antagonist is selective for the M1and/or M3 receptors over the M2 receptor. Preferably the antagonistlacks significant M2 antagonist activity. In particular preferably theantagonist activity at M1 or M3 is at least 10 times that (morepreferably 100 times that) of the antagonist activity at the M2receptor. Preferably the antagonist is a more potent antagonist of M3than M1. Preferably the antagonist has essentially no affinity for theM2 receptor.

Examples of muscarinic receptor antagonists include ipratropium salts,especially ipratropium bromide and oxitropium salts, especiallyoxitropium bromide. Preferably the muscarinic receptor antagonist islong acting, that it to say it has a duration of action sufficient toprovide a therapeutic effect when dosed once or twice per day,especially once per day (i.e. it has a therapeutic effect over 24hours). Example of a long acting muscarinic receptor antagonists includethose described in EP 418716 (Boehringer Ingelheim) such as tiotropiumand salts thereof, especially tiotopium bromide. Other examples includethose described in WO01/04118 (Almirall) such as those of formula (A)given below:

wherein:

-   © is a phenyl ring, a C₄ to C₉ heteroaromatic group containing one    or more heteroatoms (preferably selected from nitrogen, oxygen and    sulphur atoms), or a naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or    biphenyl group;-   R¹, R² and R³ each independently represent a hydrogen or halogen    atom, or a hydroxy group, or a phenyl, —OR⁴, —SR⁴, —NR⁴R⁵, —NHCOR⁴,    —CONR⁴R⁵, —CN, —NO₂, —COOR⁴ or —CF₃ group, or a straight or branched    lower alkyl group which may optionally be substituted, for example,    with a hydroxy or alkoxy group, wherein R⁴ and R⁵ each independently    represent a hydrogen atom, straight or branched lower alkyl group,    or together form an alicyclic ring; or R¹ and R² together form an    aromatic, alicyclic or heterocyclic ring;-   n is an integer from 0 to 4;-   A represents a —CH₂—, —CH═CR⁶—, —CR⁶═CH—, —CR⁶R⁷—, —CO—, —O—, —S—,    —S(O)—, SO₂ or —NR⁶— group, wherein R⁶ and R⁷ each independently    represent a hydrogen atom, straight or branched lower alkyl group,    or R⁶ and R⁷ together form an alicyclic ring;-   m is an integer from 0 to 8; provided that when m=0, A is not —CH₂—;-   p is an integer from 1 to 2 and the substitution in the    azoniabicyclic ring may be in the 2, 3 or 4 position including all    possible configurations of the asymmetric carbons;-   B represents a group of formula (i) or (ii):    wherein R¹⁰ represents a hydrogen atom, a hydroxy or methyl group;    and R¹ and R⁹ each independently represents one of the following 5    moieties:    wherein R¹¹ represents a hydrogen or halogen atom, or a straight or    branched lower alkyl group and Q represents a single bond, —CH₂—,    —CH₂—CH₂—, —O—, —O—CH₂—, —S—, —S—CH₂— or —CH═CH—, and when (i)    or (i) contain a chiral centre they may represent either    configuration;-   X represent a pharmaceutically acceptable anion of a mono or    polyvalent acid.

In the definition of compounds of formula (A), preferably lower alkylmeans C₁₋₆alkyl, more preferably C₁₋₄alkyl. Preferably alicyclic andheterocyclic rings comprise 3-10, more preferably 5-7 members.Preferably aromatic rings contain 6-14 members, especially 6 or 10members.

In the quaternary ammonium compounds of formula (A) an equivalent ofanion (X—) is associated with the positive charge of the N atom. X maybe an anion of various mineral acids. More preferably X is chloride,bromide or trifluoroacetate, especially bromide.

All stereoisomers at asymmetic centres are included within thedefinition of compounds of formula (A).

Preferred compounds of formula (A) are those wherein © represent aphenyl, pyrrolyl, or thienyl group; R¹, R² and R³ each independentlyrepresent a hydrogen atom, a hydroxy group or a halogen atom, whereinthe halogen atom is preferably fluorine; n=0 or 1; m is an integer from1 to 6, particularly 1, 2 or 3; A represents a —CH₂—, —CH═CH— or —O—group.

In formula (A) it is also preferred that p=2 and the substituent group—OC(O)B attached to the azoniabicyclo[2.2.2]octane is at the 3 position,preferably having the (R) configuration.

Especially preferred compounds are those wherein the —OC(O)B group informula (A) is diphenylacetoxy, 2-hydroxy-2,2-diphenyl-acetoxy,2,2-diphenylpropionyloxy, 2-hydroxy-2-phenyl-2-thien-2-yl-acetoxy,2-furan-2-yl-2-hydroxy-2-phenylacetoxy, 2,2-dithien-2-ylacetoxy,2-hydroxy-2,2-di-thien-2-ylacetoxy, 2-hydroxy-2,2-di-thien-3-ylacetoxy,9-hydroxy-9[H]-fluorene-9-carbonyloxy,9-methyl-9[H]-fluorene-9-carbonyloxy, 9[H]-xanthene-9-carbonyloxy,9-hydroxy-9 [H]-xanthene-9-carbonyloxy or9-methyl-9[H]-xanthene-9-carbonyloxy.

The most preferred compounds of formula (A) are those wherein theazoniabicyclo group is substituted on the nitrogen atom with a3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl,4-phenylbutyl, 3-phenylpropyl, 3-[2-hydroxyphenoxy]propyl,3-[4-fluorophenoxy]propyl, 2-benzyloxyethyl, 3-pyrrol-1-ylpropyl,2-thien-2-ylethyl, 3-thien-2-ylpropyl, 3-phenylaminopropyl,3-(methylphenylamino)propyl, 3-phenylsulfanylpropyl, 3-o-tolyloxypropyl,3-(2,4,6-trimethylphenoxy)propyl,3-(2-tert-butyl-6-methylphenoxy)propyl, 3-(biphenyl-4-yloxy)propyl,3-(5,6,7,8-tetrahydronaphthalen-2-yloxy)-propyl,3-(naphthalen-2-yloxy)-propyl, 3-(naphthalen-1-yloxy)propyl,3-(2-chlorophenoxy)propyl, 3-(2,4-difluorophenoxy)propyl,3-(3-trifluoromethyl phenoxy)propyl, 3-(3-cyanophenoxy)propyl,3-(4-cyanophenoxy)propyl, 3-(3-methoxyphenoxy)propyl,3-(4-methoxyphenoxy)propyl, 3-(benzo[1,3]dioxol-5-yloxy)propyl,3-(2-carbamoylphenoxy)propyl, 3-(3-dimethylaminophenoxy)propyl,3-(4-nitrophenoxy)propyl, (3-nitrophenoxy)propyl,3-(4-acetylaminophenoxy)propyl, 3-(3-methoxycarbonylphenoxy)propyl,3-[4-(3-hydroxypropyl)phenoxy]propyl, 3-(2-hydroxymethylphenoxy)propyl,3-(3-hydroxymethylphenoxy) propyl, 3-(4-hydroxyphenoxy)propyl,3-(2-hydroxyphenoxy)propyl, 3-(4-hydroxyphenoxy)propyl,3-(3-hydroxyphenoxy)propyl, 4-oxo thien-2-ylbutyl,3-(1-methyl-[1H]-imidazol-2-ylsulfanyl)propyl,3-(benzothiazol-2-yloxy)propyl, 3-benzyloxypropyl,6-(4-phenylbutoxy)hexyl, 4-phenoxybutyl, or 2-benzyloxypropyl.Especially preferred compounds are those wherein the azoniabicyclo groupis substituted on the nitrogen atom with a 3-phenoxypropyl,2-phenoxypropyl, 3-phenylallyl, phenethyl, 4-phenylbutyl,3-phenylpropyl, 3-[2-hydroxyphenoxy]propyl, 3-[4-flurophenoxy]propyl,2-benzyloxyethyl, 3-pyrrol-1-ylpropyl, 2-thien-2-ylethyl or3-thien-2-ylpropyl group.

Compound (I) undergoes highly efficient hepatic metabolism to yield the17-β carboxylic acid (X) as the sole major metabolite in rat and humanin vitro systems. This metabolite has been synthesised and demonstratedto be >1000 fold less active than the parent compound in in vitrofunctional glucocorticoid assays.

This efficient hepatic metabolism is reflected by in vivo data in therat, which have demonstrated plasma clearance at a rate approachinghepatic blood flow and an oral bioavailability of <1%, consistent withextensive first-pass metabolism.

In vitro metabolism studies in human hepatocytes have demonstrated thatcompound (I) is metabolised in an identical manner to fluticasonepropionate but that conversion of (I) to the inactive acid metaboliteoccurs approximately 5-fold more rapidly than with fluticasonepropionate. This very efficient hepatic inactivation would be expectedto minimise systemic exposure in man leading to an improved safetyprofile.

Inhaled steroids are also absorbed through the lung and this route ofabsorption makes a significant contribution to systemic exposure.Reduced lung absorption could therefore provide an improved safetyprofile. Studies with compound of formula (I) have shown significantlylower exposure to compound of formula (I) than with fluticasonepropionate after dry powder delivery to the lungs of anaesthetised pigs.

An improved safety profile is believed to allow compositions containingthe compound of formula (I) to demonstrate the desired anti-inflammatoryeffects when administered once-per day. Once-per-day dosing isconsidered to be significantly more convenient to patients than thetwice-per day dosing regime that is normally employed for fluticasonepropionate.

Examples of disease states in which the composition of the invention hasutility include skin diseases such as eczema, psoriasis, allergicdermatitis, neurodermatitis, pruritis and hypersensitivity reactions;inflammatory conditions of the nose, throat or lungs such as asthma(including allergen-induced asthmatic reactions), rhinitis (includinghayfever), nasal polyps, chronic obstructive pulmonary disease (COPD),interstitial lung disease, and fibrosis; inflammatory bowel conditionssuch as ulcerative colitis and Crohn's disease; and auto-immune diseasessuch as rheumatoid arthritis.

The composition of the invention may also have anti-tussive properties.

The composition of the invention is expected to be most useful in thetreatment of inflammatory disorders of the respiratory tract eg asthmaand COPD, particularly COPD.

It will be appreciated by those skilled in the art that reference hereinto treatment extends to prophylaxis as well as the treatment ofestablished conditions.

As mentioned above, the composition of the invention is useful in humanor veterinary medicine, in particular as an anti-inflammatory andanti-allergic agent.

There is thus provided as a further aspect of the invention thecomposition of the invention for use in human or veterinary medicine,particularly in the treatment of patients with inflammatory and/orallergic conditions, especially for treatment once-per-day.

According to another aspect of the invention, there is provided the useof the composition of the invention for the manufacture of a medicamentfor the treatment of patients with inflammatory and/or allergicconditions, especially for treatment once-per-day.

In a further or alternative aspect, there is provided a method for thetreatment of a human or animal subject with an inflammatory and/orallergic condition, which method comprises administering to said humanor animal subject an effective amount of the composition of theinvention especially for administration once-per-day.

The composition of the invention may be formulated for administration inany convenient way, and the invention therefore also includes within itsscope pharmaceutical compositions comprising the compound of formula (I)or a physiologically acceptable solvate thereof, a muscarinic receptorantagonist together, if desirable, in admixture with one or morephysiologically acceptable diluents or carriers. Pharmaceuticalcompositions suitable for once-per-day administration are of particularinterest. Formulations are preferably administered by inhalationtopically to the lung.

Further, there is provided a process for the preparation of suchpharmaceutical compositions which comprises mixing the ingredients.

The compound according to the invention may, for example, be formulatedfor oral, buccal, sublingual, parenteral, local or rectaladministration, especially local administration.

Local administration as used herein, includes administration byinsufflation and inhalation. Examples of various types of preparationfor local administration include ointments, lotions, creams, gels,foams, preparations for delivery by transdermal patches, powders,sprays, aerosols, capsules or cartridges for use in an inhaler orinsufflator or drops (eg eye or nose drops), solutions/suspensions fornebulisation, suppositories, pessaries, retention enemas and chewable orsuckable tablets or pellets (eg for the treatment of aphthous ulcers) orliposome or microencapsulation preparations.

Advantageously compositions for topical administration to the lunginclude dry powder compositions and spray compositions.

Dry powder compositions for topical delivery to the lung by inhalationmay, for example, be presented in capsules and cartridges for use in aninhaler or insufflator of, for example, gelatine. Formulations generallycontain a powder mix for inhalation of the compound of the invention anda suitable powder base (carrier substance) such as lactose or starch.Use of lactose is preferred. Each capsule or cartridge may generallycontain between 20 μg-10 mg of the compound of formula (I) and themuscarinic receptor antagonist. Alternatively, the compound of theinvention may be presented without excipients. Packaging of theformulation may be suitable for unit dose or multi-dose delivery. In thecase of multi-dose delivery, the formulation can be pre-metered (eg asin Diskus, see GB 2242134 or Diskhaler, see GB 2178965, 2129691 and2169265) or metered in use (eg as in Turbuhaler, see EP 69715). Anexample of a unit-dose device is Rotahaler (see GB 2064336). The Diskusinhalation device comprises an elongate strip formed from a base sheethaving a plurality of recesses spaced along its length and a lid sheethermetically but peelably sealed thereto to define a plurality ofcontainers, each container having therein an inhalable formulationcontaining a compound of formula (I) and the muscarinic receptorantagonist preferably combined with lactose. Preferably, the strip issufficiently flexible to be wound into a roll. The lid sheet and basesheet will preferably have leading end portions which are not sealed toone another and at least one of the said leading end portions isconstructed to be attached to a winding means. Also, preferably thehermetic seal between the base and lid sheets extends over their wholewidth. The lid sheet may preferably be peeled from the base sheet in alongitudinal direction from a first end of the said base sheet.

Spray compositions for topical delivery to the lung by inhalation mayfor example be formulated as aqueous solutions or suspensions or asaerosols delivered from pressurised packs, such as a metered doseinhaler, with the use of a suitable liquefied propellant. Aerosolcompositions suitable for inhalation can be either a suspension or asolution and generally contain the compound of formula (I) and themuscarinic receptor antagonist and a suitable propellant such as afluorocarbon or hydrogen-containing chlorofluorocarbon or mixturesthereof, particularly hydrofluoroalkanes, especially1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or amixture thereof. The aerosol composition may optionally containadditional formulation excipients well known in the art such assurfactants eg oleic acid or lecithin and cosolvents eg ethanol. Oneexample formulation is excipient free and consists essentially of (egconsists of) compound of formula (I) (preferably in unsolvated form egas Form 1), a muscarinic receptor antagonist (optionally together with afurther active ingredient) and a propellant selected from1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane andmixture thereof. Another example formulation comprises particulatecompound of formula (I), a propellant selected from1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane andmixture thereof and a suspending agent which is soluble in thepropellant eg an oligolactic acid or derivative thereof as described inWO94/21229. The preferred propellant is 1,1,1,2-tetrafluoroethane.Pressurised formulations will generally be retained in a canister (eg analuminium canister) closed with a valve (eg a metering valve) and fittedinto an actuator provided with a mouthpiece.

Medicaments for administration by inhalation desirably have a controlledparticle size. The optimum particle size for inhalation into thebronchial system is usually 1-10 μm, preferably 2-5 μm. Particles havinga size above 20 μm are generally too large when inhaled to reach thesmall airways. To achieve these particle sizes the particles of compoundof formula (I) and the muscarinic receptor antagonist (and any furthertherapeutically active ingredient) as produced may be size reduced byconventional means eg by micronisation. The desired fraction may beseparated out by air classification or sieving. Preferably, theparticles will be crystalline, prepared for example by a process whichcomprises mixing in a continuous flow cell in the presence of ultrasonicradiation a flowing solution of compound of formula (I) and themuscarinic receptor antagonist as medicament (either separately ortogether) in a liquid solvent with a flowing liquid antisolvent for saidmedicament (eg as described in International Patent ApplicationPCT/GB99/04368) or else by a process which comprises admitting a streamof solution of the substance in a liquid solvent and a stream of liquidantisolvent for said substance tangentially into a cylindrical mixingchamber having an axial outlet port such that said streams are therebyintimately mixed through formation of a vortex and precipitation ofcrystalline particles of the substance is thereby caused (eg asdescribed in International Patent Application PCT/GB00/04327). When anexcipient such as lactose is employed, generally, the particle size ofthe excipient will be much greater than the inhaled medicament withinthe present invention. When the excipient is lactose it will typicallybe present as milled lactose, wherein not more than 85% of lactoseparticles will have a MMD of 60-90 μm and not less than 15% will have aMMD of less than 15 μm.

Formulations for administration topically to the lung or nose includepressurised aerosol formulations and aqueous formulations administeredto the nose by pressurised pump. Aqueous formulations for administrationto the lung or nose may be provided with conventional excipients such asbuffering agents, tonicity modifying agents and the like. Aqueousformulations may also be administered to the lung and nose bynebulisation.

Other possible presentations include the following:

Ointments, creams and gels, may, for example, be formulated with anaqueous or oily base with the addition of suitable thickening and/orgelling agent and/or solvents. Such bases may thus, for example, includewater and/or an oil such as liquid paraffin or a vegetable oil such asarachis oil or castor oil, or a solvent such as polyethylene glycol.Thickening agents and gelling agents which may be used according to thenature of the base include soft paraffin, aluminium stearate,cetostearyl alcohol, polyethylene glycols, woolfat, beeswax,carboxypolymethylene and cellulose derivatives, and/or glycerylmonostearate and/or non-ionic emulsifying agents.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents or thickening agents.

Powders for external application may be formed with the aid of anysuitable powder base (carrier substance), for example, talc, lactose orstarch. Drops may be formulated with an aqueous or non-aqueous base alsocomprising one or more dispersing agents, solubilising agents,suspending agents or preservatives.

If appropriate, the formulations of the invention may be buffered by theaddition of suitable buffering agents.

The proportion of the active compound of formula (I) and the muscarinicreceptor antagonist in the local compositions according to the inventiondepends on the precise type of formulation to be prepared but willgenerally be within the range of from 0.001 to 10% by weight. Generally,however for most types of preparations advantageously the proportionused will be within the range of from 0.005 to 1%. However, in powdersfor inhalation or insufflation the proportion used will usually bewithin the range of from 0.01 to 5%.

Aerosol formulations are preferably arranged so that each metered doseor “puff” of aerosol contains 1 μg-2000 μg eg 20 μg-2000 μg, preferablyabout 20 μg-500 μg of a compound of formula (I). Administration may beonce daily or several times daily, for example 2, 3, 4 or 8 times,giving for example 1, 2 or 3 doses each time. Preferably the compound offormula (I) is delivered once or twice daily, more preferablyonce-per-day. The overall daily dose with an aerosol will typically bewithin the range 10 μg-10 mg eg 100 μg-10 mg preferably, 200 μg-2000 μg.

Muscarinic receptor antagonists will be dosed in an amount depending onthe potency and safety of the compound involved. For example ipratropiumand salts thereof (eg ipratropium bromide) is usually dosed at around 40μg-320 μg per day (say 1-8 puffs of 40 μg per day); oxitropium and saltsthereof (eg oxitropium bromide) is usually dosed at around 100 μg-640 μgper day (say 16 puffs of 100 μg per day); tiotropium and salts thereof(eg tiotropium bromide) is usually dosed at around 10 μg-50 μg per day(say 1-4 puffs of 10 μg per day); compounds of formula (A) may be dosedin an amount of 100 μg-1200 μg per day.

Since the compound of formula (I) is long-acting, preferably thecomposition of the invention will be delivered once-per-day and the doseof each of the active ingredients will be selected so that the compoundhas a therapeutic effect in the treatment of respiratory disorders (egasthma or COPD, particularly asthma) over 24 hours or more.

Topical preparations may be administered by one or more applications perday to the affected area; over skin areas occlusive dressings mayadvantageously be used. Continuous or prolonged delivery may be achievedby an adhesive reservoir system.

For internal administration the compound according to the invention may,for example, be formulated in conventional manner for oral, parenteralor rectal administration. Formulations for oral administration includesyrups, elixirs, powders, granules, tablets and capsules which typicallycontain conventional excipients such as binding agents, fillers,lubricants, disintegrants, wetting agents, suspending agents,emulsifying agents, preservatives, buffer salts, flavouring, colouringand/or sweetening agents as appropriate. Dosage unit forms are, however,preferred as described below.

Preferred forms of preparation for internal administration are dosageunit forms i.e. tablets and capsules. Such dosage unit forms containfrom 0.1 mg to 20 mg preferably from 2.5 to 10 mg of the composition ofthe invention.

The compound according to the invention may in general may be given byinternal administration in cases where systemic adreno-cortical therapyis indicated.

In general terms preparations, for internal administration may containfrom 0.05 to 10% of the active ingredient dependent upon the type ofpreparation involved. The daily dose may vary from 0.1 mg to 60 mg, eg5-30 mg, dependent on the condition being treated, and the duration oftreatment desired.

Slow release or enteric coated formulations may be advantageous,particularly for the treatment of inflammatory bowel disorders.

The pharmaceutical compositions according to the invention may also beused in combination with another therapeutically active agent, forexample, a β₂ adrenoreceptor agonist, an anti-histamine or ananti-allergic. The invention thus provides, in a further aspect, acombination comprising the composition of the invention together withanother therapeutically active agent, for example, a β₂-adrenoreceptoragonist, an anti-histamine or an anti-allergic.

Examples of β₂-adrenoreceptor agonists include salmeterol (eg asracemate or a single enantiomer such as the R-enantiomer), salbutamol,formoterol, salmefamol, fenoterol or terbutaline and salts thereof, forexample the xinafoate salt of salmeterol, the sulphate salt or free baseof salbutamol or the fumarate salt of formoterol.

Pharmaceutical compositions employing compositions of the invention incombination with long-acting β₂-adrenoreceptor agonists are particularlypreferred, especially those which have a therapeutic effect (eg in thetreatment of asthma or COPD, particularly asthma) over 24 hours or more.

Particularly preferred long acting β₂-adrenoreceptor agonists includethose described in WO 02066422, WO02070490 and WO02076933.

Especially preferred long-acting β₂-adrenoreceptor agonists includecompounds of formula(M):

or a salt or solvate thereof, wherein:

-   m is an integer of from 2 to 8;-   n is an integer of from 3 to 11, with the proviso that m+n is 5 to    19,-   R¹¹ is —XSO₂NR¹⁶R¹⁷ wherein X is —(CH₂)_(p)— or C₂₋₆ alkenylene;-   R¹⁶ and R¹⁷ are independently selected from hydrogen, C₁₋₆alkyl,    C₃₋₇cycloalkyl, C(O)NR¹⁸R¹⁹, phenyl, and phenyl (C₁₋₄alkyl)-,-   or R¹⁶ and R¹⁷, together with the nitrogen to which they are bonded,    form a 5-, 6-, or 7-membered nitrogen containing ring, and R¹⁶ and    R¹⁷ are each optionally substituted by one or two groups selected    from halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, hydroxy-substituted    C₁₋₆alkoxy, —CO₂R¹⁸, —SO₂NR¹⁸R¹⁹, —CON R¹⁸R¹⁹, —NR¹⁸C(O)R¹⁹, or a    5-, 6 or 7-membered heterocylic ring;-   R¹⁸ and R¹⁹ are independently selected from hydrogen, C₁₋₆alkyl,    C₃₋₆cycloalkyl, phenyl, and phenyl (C₁₋₄alkyl)-; and-   p is an integer of from 0 to 6, preferably from 0 to 4;-   R¹² and R¹³ are independently selected from hydrogen, C₁₋₆alkyl,    C₁₋₆alkoxy, halo, phenyl, and C₁₋₆haloalkyl; and-   R¹⁴ and R¹⁵ are independently selected from hydrogen and C₁₋₄alkyl    with the proviso that the total number of carbon atoms in R¹⁴ and    R¹⁵ is not more than 4.

Since the compound of formula (I) is long-acting, preferably thecomposition comprising the compound of formula (I), the muscarinicreceptor antagonist (especially a long acting muscarinic receptorantagonist) and the long-acting β₂-adrenoreceptor agonists will bedelivered once-per-day and the dose of each will be selected so that thecomposition has a therapeutic effect in the treatment of respiratorydisorders effect (eg in the treatment of asthma or COPD, particularlyasthma) over 24 hours or more.

Examples of anti-histamines include methapyrilene or loratadine.

Other suitable combinations include, for example, otheranti-inflammatory agents eg. NSAIDs (eg. PDE4 inhibitors, leukotrieneantagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2integrin antagonists and adenosine 2a agonists)) or antiinfective agents(eg. antibiotics, antivirals).

Of particular interest is use of the compounds of formula (I) incombination with a phosphodiesterase 4 (PDE4) inhibitor. ThePDE4-specific inhibitor useful in this aspect of the invention may beany compound that is known to inhibit the PDE4 enzyme or which isdiscovered to act as a PDE4 inhibitor, and which are only PDE4inhibitors, not compounds which inhibit other members of the PDE familyas well as PDE4. Generally it is preferred to use a PDE4 inhibitor whichhas an IC₅₀ ratio of about 0.1 or greater as regards the IC₅₀ for thePDE4 catalytic form which binds rolipram with a high affinity divided bythe IC₅₀ for the form which binds rolipram with a low affinity. For thepurposes of this disclosure, the cAMP catalytic site which binds R and Srolipram with a low affinity is denominated the “low affinity” bindingsite (LPDE 4) and the other form of this catalytic site which bindsrolipram with a high affinity is denominated the “high affinity” bindingsite (HPDE 4). This term “HPDE4” should not be confused with the term“hPDE4” which is used to denote human PDE4.

A method for determining IC50 ratios is set out in U.S. Pat. No.5,998,428 which is herein incorporated in full by reference as thoughset out herein. See also PCT application WO 00/51599 for anotherdescription of the assay.

The preferred PDE4 inhibitors of use in this invention will be thosecompounds which have a salutary therapeutic ratio, i.e., compounds whichpreferentially inhibit cAMP catalytic activity where the enzyme is inthe form that binds rolipram with a low affinity, thereby reducing theside effects which apparently are linked to inhibiting the form whichbinds rolipram with a high affinity. Another way to state this is thatthe preferred compounds will have an IC₅₀ ratio of about 0.1 or greateras regards the IC₅₀ for the PDE4 catalytic form which binds rolipramwith a high affinity divided by the IC₅₀ for the form which bindsrolipram with a low affinity.

A further refinement of this standard is that of one wherein the PDE4inhibitor has an IC₅₀ ratio of about 0.1 or greater, said ratio is theratio of the IC₅₀ value for competing with the binding of 1 nM of[³H]R-rolipram to a form of PDE4 which binds rolipram with a highaffinity over the IC₅₀ value for inhibiting the PDE4 catalytic activityof a form which binds rolipram with a low affinity using 1 μM[³H]-cAMPas the substrate.

Most preferred are those PDE4 inhibitors which have an IC₅₀ ratio ofgreater than 0.5, and particularly those compounds having a ratio ofgreater than 1.0. Preferred compounds are cis4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-oneandcis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol];these are examples of compounds which bind preferentially to the lowaffinity binding site and which have an IC₅₀ ratio of 0.1 or greater.

Other compounds of interest include:

Compounds set out in U.S. Pat. No. 5,552,438 issued 3 Sep. 1996; thispatent and the compounds it discloses are incorporated herein in full byreference. The compound of particular interest, which is disclosed inU.S. Pat. No. 5,552,438, iscis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid (also known as cilomalast) and its salts, esters, pro-drugs orphysical forms; AWD-12-281 from elbion (Hofgen, N. et al. 15th EFMC IntSymp Med Chem (September 6-10, Edinburgh) 1998, Abst P.98); a9-benzyladenine derivative nominated NCS-613 (INSERM); D-4418 fromChiroscience and Schering-Plough; a benzodiazepine PDE4 inhibitoridentified as CI-1018 (PD-168787; Parke-Davis/Warner-Lambert); abenzodioxole derivative Kyowa Hakko disclosed in WO 9916766; V-11294Afrom Napp (Landells, L. J. et al. Eur Resp J [Annu Cong Eur Resp Soc(September 19-23, Geneva) 1998] 1998, 12(Suppl. 28): Abst P2393);roflumilast (CAS reference No 162401-32-3) and a pthalazinone (WO9947505) from Byk-Gulden; or a compound identified as T-440 (TanabeSeiyaku; Fuji, K. et al. J Pharmacol Exp Ther, 1998, 284(1): 162).

The invention thus provides, in a further aspect, a combinationcomprising the composition of the invention together with a PDE4inhibitor.

The combination referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with aphysiologically acceptable diluent or carrier represent a further aspectof the invention.

The compound according to the invention in combination with anothertherapeutically active ingredient as described above may be formulatedfor administration in any convenient way, and the invention thereforealso includes within its scope pharmaceutical compositions comprisingthe composition of the invention in combination with anothertherapeutically active ingredient together, if desirable, in admixturewith one or more physiologically acceptable diluents or carriers. Thepreferred route of administration for inflammatory disorders of therespiratory tract will generally be administration by inhalation.

The pharmaceutical composition of the invention may further comprise oneor more excipients.

By the term “excipient”, as used herein, it is meant to meansubstantially inert materials that are nontoxic and do not interact withother components of a composition in a deleterious manner including, butnot limited to, pharmaceutical grades of: carbohydrates, organic andinorganic salts, polymers, amino acids, phospholipids, wetting agents,emulsifiers, surfactants, poloxamers, pluronics, and ion exchangeresins, and combinations thereof, a non-exhaustive list of examples ofwhich are provided below:

-   Carbohydrates, including: monosaccharides, such as, but not limited    to, fructose disaccharides, such as, but not limited to lactose, and    combinations and derivatives thereof; polysaccharides, such as, but    not limited to, cellulose and combinations and derivatives thereof;    oligosaccharides, such as, but not limited to, dextrins, and    combinations and derivatives thereof; polyols, such as but not    limited to sorbitol, and combinations and derivatives thereof;-   Organic and inorganic salts, including but not limited to sodium or    calcium phosphates, magnesium stearate, and combinations and    derivatives thereof;-   Polymers, including: natural biodegradable protein polymers    including, but not limited to, gelatin and combinations and    derivatives thereof; Natural biodegradable polysaccharide polymers    including, but not limited to, chitin and starch, crosslinked    starch, and combinations and derivatives thereof; Semisynthetic    biodegradable polymers including, but not limited to, derivatives of    chitosan; Synthetic biodegradable polymers including but not limited    to polyethylene glycols (PEG), polylactic acid (PLA), synthetic    polymers including but not limited to polyvinyl alcohol and    combinations and derivatives thereof;-   Amino acids including but not limited to including non-polar amino    acids, such as leucine and combinations and derivatives thereof;-   Phospholipids, including lecithins and combinations and derivatives    thereof;-   Wetting agents/Surfactants/Emulsifiers, including, but not limited    to gum acacia, cholesterol, fatty acids including, combinations and    derivatives thereof;-   Poloxamers/Pluronics: including but not limited to poloxamer 188,    Pluronic® F-108, and combinations and derivations thereof;-   Ion exchange resins: including but not limited to amberlite IR120    and combinations and derivatives thereof;    and combinations of the noted excipients.

Further, there is provided a process for the preparation of suchpharmaceutical compositions which comprises mixing the ingredients.

Appropriate doses of known therapeutic agents will be readilyappreciated by those skilled in the art.

Compounds may be tested for their muscarinic receptor antagonistactivity by reference to methods disclosed in E-B Haddad et al (1994) JMol Pharmacol 45, 899 and references cited therein.

Compounds of formula (A) may be prepared following methods described inWO01/04118. Tiotropium, ipratropium and oxitropium and salts thereof maybe prepared following methods described in Merck Index.

A process for preparing a compound of formula (I) comprises alkylationof a thioacid of formula (II)

or a salt thereof.

In this process the compound of formula (II) may be reacted with acompound of formula FCH₂L wherein L represents a leaving group (eg ahalogen atom, a mesyl or tosyl group or the like) for example, anappropriate fluoromethyl halide under standard conditions. Preferably,the fluoromethyl halide reagent is bromofluoromethane. Preferably thecompound of formula (II) is employed as a salt, particularly the saltwith diisopropylethylamine.

In a preferred process for preparing the compound of formula (I), thecompound of formula (II) or a salt thereof is treated withbromofluoromethane optionally in the presence of a phase transfercatalyst. A preferred solvent is methylacetate, or more preferablyethylacetate, optionally in the presence of water. The presence of waterimproves solubility of both starting material and product and the use ofa phase transfer catalyst results in an increased rate of reaction.Examples of phase transfer catalysts that may be employed include (butare not restricted to) tetrabutylammonium bromide, tetrabutylammoniumchloride, benzyltributylammonium bromide, benzyltributylammoniumchloride, benzyltriethylammonium bromide, methyltributylammoniumchloride and methyltrioctylammonium chloride. THF has also successfullybeen employed as solvent for the reaction wherein the presence of aphase transfer catalyst again provides a significantly faster reactionrate. Preferably the product present in an organic phase is washedfirstly with aqueous acid eg dilute HCl in order to remove aminecompounds such as triethylamine and diisopropylethylamine and then withaqueous base eg sodium bicarbonate in order to remove any unreactedprecursor compound of formula (II).

Compound of formula (I) in unsolvated form may be prepared by a processcomprising:

-   (a) Crystallising the compound of formula (I) in the presence of a    non-solvating solvent such as ethanol, methanol, water, ethyl    acetate, toluene, methylisobutylketone or mixtures thereof; or-   (b) Desolvating a compound of formula (I) in solvated form (eg in    the form of a solvate with acetone, isopropanol, methylethylketone,    DMF or tetrahydrofuran) eg by heating.

In step (b) the desolvation will generally be performed at a temperatureexceeding 50° C. preferably at a temperature exceeding 100° C. Generallyheating will be performed under vacuum.

Compound of formula (I) in unsolvated form has been found to exist in 3crystalline polymorphic forms, Forms 1, 2 and 3, although Form 3 may bean unstable variant of Form 2. The Forms are characterised by theirX-ray diffraction (XRPD) patterns Broadly speaking the Forms arecharacterised in their XRPD profiles as follows:

-   Form 1: Peak at around 18.9 degrees 2Theta-   Form 2: Peaks at around 18.4 amd 21.5 degrees 2Theta-   Form 3: Peaks at around 18.6 and 19.2 degrees 2Theta.

Forms 1 appears likely to be the thermodynamically most stable formsince Forms 2 and 3 are converted into Form 1 on heating.

Preferably compositions of the invention employ the compound of formula(I) in unsolvated form, especially as polymorph Form 1.

A process for preparing a compound of formula (I) as unsolvated Form 1polymorph comprises dissolving compound of formula (I) inmethylisobutylketone, ethyl acetate or methyl acetate and producingcompound of formula (I) as unsolvated Form 1 by addition of anon-solvating anti-solvent such as iso-octane or toluene.

According to a first preferred embodiment of this process the compoundof formula (I) may be dissolved in ethyl acetate and compound of formula(I) as unsolvated Form 1 polymorph may be obtained by addition oftoluene as anti-solvent. In order to improve the yield, preferably theethyl acetate solution is hot and once the toluene has been added themixture is distilled to reduce the content of ethyl acetate.

According to a second preferred embodiment of this process the compoundof formula (I) may be dissolved in methylisobutylketone and compound offormula (I) as unsolvated Form 1 polymorph may be obtained by additionof isooctane as anti-solvent.

Compound of formula (I) in solvated form may be prepared bycrystallising the compound of formula (I) from a solvating solvent suchas acetone or tetrahydrofuran (THF).

Compounds of formula (II) may be prepared from the corresponding17α-hydroxyl derivative of formula (III):

using for example, the methodology described by G. H. Phillipps et al.,(1994) Journal of Medicinal Chemistry, 37, 3717-3729. For example thestep typically comprises the addition of a reagent suitable forperforming the esterification eg an activated derivative of 2-furoicacid such as an activated ester or preferably a 2-furoyl halide eg2-furoyl chloride (employed in at least 2 times molar quantity relativeto the compound of formula (III)) in the presence of an organic base egtriethylamine. The second mole of 2-furoyl chloride reacts with thethioacid moiety in the compound of formula (III) and needs to be removedeg by reaction with an amine such as diethylamine.

This method suffers disadvantages, however, in that the resultantcompound of formula (II) is not readily purified of contamination withthe by-product 2-furoyidiethylamide. We have therefore invented severalimproved processes for performing this conversion.

In a first such improved process we have discovered that by using a morepolar amine such as diethanolamine, a more water soluble by-product isobtained (in this case 2-furoyldiethanolamide) which permits compound offormula (II) or a salt thereof to be produced in high purity since theby-product can efficiently be removed by water washing.

Thus we provide a process for preparing a compound of formula (II) whichcomprises:

-   (a) reacting a compound of formula (III) with an activated    derivative of 2-furoic acid as in an amount of at least 2 moles of    the activated derivative per mole of compound of formula (III) to    yield a compound of formula (IIA);    and-   (b) removal of the sulphur-linked 2-furoyl moiety from compound of    formula (IIA) by reaction of the product of step (a) with an organic    primary or secondary amine base capable of forming a water soluble    2-furoyl amide.

In two particularly convenient embodiments of this process we alsoprovide methods for the efficient purification of the end product whichcomprise either

-   (c1) when the product of step (b) is dissolved in a substantially    water immiscible organic solvent, purifying the compound of    formula (II) by washing out the amide by-product from step (b) with    an aqueous wash, or-   (c2) when the product of step (b) is dissolved in a water miscible    solvent, purifying the compound of formula (II) by treating the    product of step (b) with an aqueous medium so as to precipitate out    pure compound of formula (II) or a salt thereof.

In step (a) preferably the activated derivative of 2-furoic acid may bean activated ester of 2-furoic acid, but is more preferably a 2-furoylhalide, especially 2-furoyl chloride. A suitable solvent for thisreaction is ethylacetate or methylacetate (preferably methylacetate)(when step (c1) may be followed) or acetone (when step (c2) may befollowed). Normally an organic base eg triethylamine will be present. Instep (b) preferably the organic base is diethanolamine. The base maysuitably be dissolved in a solvent eg methanol. Generally steps (a) and(b) will be performed at reduced temperature eg between 0 and 5° C. Instep (c1) the aqueous wash may be water, however the use of brineresults in higher yields and is therefore preferred. In step (c2) theaqueous medium is for example a dilute aqueous acid such as dilute HCl.

We also provide an alternative process for preparing a compound offormula (II) which comprises:

-   (a) reacting a compound of formula (III) with an activated    derivative of 2-furoic acid in an amount of at least 2 moles of    activated derivative per mole of compound of formula (III) to yield    a compound of formula (IIA); and-   (b) removal of the sulphur-linked 2-furoyl moiety from compound of    formula (IIA) by reaction of the product of step (a) with a further    mole of compound of formula (III) to give two moles of compound of    formula (II).

In step (a) preferably the activated derivative of 2-furoic acid may bean activated ester of 2-furoic acid, but is more preferably a 2-furoylhalide, especially 2-furoyl chloride. A suitable solvent for his step isacetone. Normally an organic base eg triethylamine will be present. Instep (b) a suitable solvent is DMF or dimethylacetamide. Normally anorganic base eg triethylamine will be present. Generally steps (a) and(b) will be performed at reduced temperature eg between 0 and 5° C. Theproduct may be isolated by treatment with acid and washing with water.

This aforementioned process is very efficient in that it does notproduce any furoylamide by-product (thus affording inter aliaenvironmental advantages) since the excess mole of furoyl moiety istaken up by reaction with a further mole of compound of formula (II) toform an additional mole of compound of formula (II).

Further general conditions for the conversion of compound of formula(III) to compound of formula (II) in the two processes just describedwill be well known to persons skilled in the art.

According to a preferred set of conditions, however, we have found thatthe compound of formula (II) may advantageously be isolated in the formof a solid crystalline salt. The preferred salt is a salt formed with abase such as triethylamine, 2,4,6-trimethylpyridine,diisopropylethylamine or N-ethylpiperidine. Such salt forms of compoundof formula (II) are more stable, more readily filtered and dried and canbe isolated in higher purity than the free thioacid. The most preferredsalt is the salt formed with diisopropylethylamine. The triethylaminesalt is also of interest.

Compounds of formula (III) may be prepared in accordance with proceduresdescribed in GB 2088877B. Compounds of formula (III) may also beprepared by a process comprising the following steps:

Step (a) comprises oxidation of a solution containing the compound offormula (V). Preferably, step (a) will be performed in the presence of asolvent comprising methanol, water, tetrahydrofuran, dioxan ordiethylene glygol dimethylether. So as to enhance yield and throughput,preferred solvents are methanol, water or tetrahydrofuran, and morepreferably are water or tetrahydrofuran, especially water andtetrahydrofuran as solvent. Dioxan and diethylene glygol dimethyletherare also preferred solvents which may optionally (and preferably) beemployed together with water. Preferably, the solvent will be present inan amount of between 3 and 10 vol relative to the amount of the startingmaterial (1 wt.), more preferably between 4 and 6 vol., especially 5vol. Preferably the oxidising agent is present in an amount of 1-9 molarequivalents relative to the amount of the starting material. Forexample, when a 50% w/w aqueous solution of periodic acid is employed,the oxidising agent may be present in an amount of between 1.1 and 10wt. relative to the amount of the starting material (1 wt.), morepreferably between 1.1 and 3 wt., especially 1.3 wt. Preferably, theoxidation step will comprise the use of a chemical oxidising agent. Morepreferably, the oxidising agent will be periodic acid or iodic acid or asalt thereof. Most preferably, the oxidising agent will be periodic acidor sodium periodate, especially periodic acid. Alternatively (or inaddition), it will also be appreciated that the oxidation step maycomprise any suitable oxidation reaction, eg one which utilises airand/or oxygen. When the oxidation reaction utilises air and/or oxygen,the solvent used in said reaction will preferably be methanol.Preferably, step (a) will involve incubating the reagents at roomtemperature or a little warmer, say around 25° C. eg for 2 hours. Thecompound of formula (IV) may be isolated by recrystallisation from thereaction mixture by addition of an anti-solvent. A suitable anti-solventfor compound of formula (IV) is water. Surprisingly we have discoveredthat it is highly desirable to control the conditions under which thecompound of formula (IV) is precipitated by addition of anti-solvent egwater. When the recrystallisation is performed using chilled water (egwater/ice mixture at a temperature of 0-5° C.) although betteranti-solvent properties may be expected we have found that thecrystalline product produced is very voluminous, resembles a soft geland is very difficult to filter. Without being limited by theory webelieve that this low density product contains a large amount ofsolvated solvent within the crystal lattice. By contrast when conditionsof around 10° C. or higher are used (eg around ambient temperature) agranular product of a sand like consistency which is very easilyfiltered is produced. Under these conditions, crystallisation typicallycommences after around 1 hour and is typically completed within a fewhours (eg 2 hours). Without being limited by theory we believe that thisgranular product contains little or no solvated solvent within thecrystal lattice.

Step (b) will typically comprise the addition of a reagent suitable forconverting a carboxylic acid to a carbothioic acid eg using hydrogensulphide gas together with a suitable coupling agent egcarbonyldiimidazole (CDI) in the presence of a suitable solvent egdimethylformamide.

The advantages of the compositions of the invention may include the factthat they appears to demonstrate excellent anti-inflammatory properties,with predictable pharmacokinetic and pharmacodynamic behaviour, with anattractive side-effect profile, long duration of action, and iscompatible with a convenient regime of treatment in human patients, inparticular being amendable to once-per day dosing. Further advantagesmay include the fact that the compositions have desirable physical andchemical properties which allow for ready manufacture and storage.

The following non-limiting Examples illustrate the invention:

EXAMPLES

General

1H-nmr spectra were recorded at 400 MHz and the chemical shifts areexpressed in ppm relative to tetramethylsilane. The followingabbreviations are used to describe the multiplicities of the signals: s(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd(doublet of doublets), ddd (doublet of doublet of doublets), dt (doubletof triplets) and b (broad). Biotage refers to prepacked silica gelcartridges containing KP-Sil run on flash 12i chromatography module.LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm×4.6 mm ID)eluting with 0.1% HCO₂H and 0.01 M ammonium acetate in water (solventA), and 0.05% HCO₂H 5% water in acetonitrile (solvent B), using thefollowing elution gradient 0-0.7 min 0% B, 0.74.2 min 100% B, 4.2-5.3min 0% B, 5.3-5.5 min 0% B at a flow rate of 3 ml/min. The mass spectrawere recorded on a Fisons VG Platform spectrometer using electrospraypositive and negative mode (ES+ve and ES−ve).

Intermediates

Intermediate 1: 6α,9α-Difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicAcid diisopropylethylamine Salt

A stirred suspension of 6α, 9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid(prepared in accordance with the procedure described in GB 2088877B)(49.5 g) in methylacetate (500 ml) is treated with triethylamine (35 ml)maintaining a reaction temperature in the range 0-5° C. 2-Furoylchloride (25 ml) is added and the mixture stirred at 0-5° C. for 1 hour.A solution of diethanolamine (52.8 g) in methanol (50 ml) is added andthe mixture stirred at 0-5° C. for at least 2 hours. Dilute hydrochloricacid (approx 1 M, 550 ml) is added maintaining a reaction temperaturebelow 15° C. and the mixture stirred at 15° C. The organic phase isseparated and the aqueous phase is back extracted with methyl acetate(2×250 ml). All of the organic phases are combined, washed sequentiallywith brine (5×250 ml) and treated with di-isopropylethylamine (30 ml).The reaction mixture is concentrated by distillation at atmosphericpressure to an approximate volume of 250 ml and cooled to 25-30° C.(crystallisation of the desired product normally occurs duringdistillation/subsequent cooling). Tertiary butyl methyl ether (TBME)(500 ml) is added, the slurry further cooled and aged at 0-5° C. for atleast 10 minutes. The product is filtered off, washed with chilled TBME(2×200 ml) and dried under vacuum at approximately 40-50° C. (75.3 g,98.7%). NMR (CDCl₃) δ: 7.54-7.46 (1H, m), 7.20-7.12 (1H, dd), 7.07-6.99(1H, dd), 6.48-6.41 (2H, m), 6.41-6.32 (1H, dd), 5.51-5.28 (1H, dddd²J_(H-F) 50 Hz), 4.45-4.33(1H, bd), 3.92-3.73 (3H, bm), 3.27-3.14 (2H,q), 2.64-2.12 (5H, m), 1.88-1.71 (2H, m), 1.58-1.15 (3H, s), 1.50-1.38(15H, m), 1.32-1.23 (1H, m), 1.23-1.15 (3H s), 1.09-0.99 (3H, d)

Intermediate 2: 6α,9α-Difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl Ester

Unsolvated Form 1

A mobile suspension of Intermediate 1 (12.61 g, 19.8 mmol) in ethylacetate (230 ml) and water (50 ml) is treated with a phase transfercatalyst (benzyltributylammonium chloride, 10 mol %), cooled to 3° C.and treated with bromofluoromethane (1.10 ml, 19.5 mmol, 0.98equivalents), washing in with prechilled (0° C.) ethyl acetate (EtOAc)(20 ml). The suspension is stirred overnight, allowing to warm to 17° C.The aqueous layer is separated and the organic phase is sequentiallywashed with 1 M HCl (50 ml), 1% w/v NaHCO₃ solution (3×50 ml) and water(2×50 ml). The ethylacetate solution is distilled at atmosphericpressure until the distillate reaches a temperature of approximately 73°C. at which point toluene (150 ml) is added. Distillation is continuedat atmospheric pressure until all remaining EtOAc has been removed(approximate distillate temperature 103° C.). The resultant suspensionis cooled and aged at <10° C. and filtered off. The bed is washed withtoluene (2×30 ml) and the product oven dried under vacuum at 60° C. toconstant weight to yield the title compound (8.77 g, 82%) LCMS retentiontime 3.66 min, m/z 539 MH⁺, NMR δ (CDCl₃) includes 7.60 (1H, m),7.18-7.11 (2H, m), 6.52 (1H, dd, J 4.2 Hz), 6.46 (1H, s), 6.41 (1H, dd,J 10, 2 Hz), 5.95 and 5.82 (2H dd, J 51, 9 Hz), 5.48 and 5.35 (1H, 2m),4.48 (1H, m), 3.48 (1H, m), 1.55 (3H, s), 1.16 (3H, s), 1.06 (3H, d, J 7Hz).

Pharmacological Activity

In Vitro Pharmacological Activity

Pharmacological activity was assessed in a functional in vitro assay ofglucocorticoid agonist activity which is generally predictive ofanti-inflammatory or anti-allergic activity in vivo.

For the experiments in this section, compound of formula (I) was used asunsolvated

Form 1 (Intermediate 2)

The functional assay was based on that described by K. P. Ray et al.,Biochem J. (1997), 328, 707-715. A549 cells stably transfected with areporter gene containing the NF-κB responsive elements from the ELAMgene promoter coupled to sPAP (secreted alkaline phosphatase) weretreated with test compounds at appropriate doses for 1 hour at 37° C.The cells were then stimulated with tumour necrosis factor (TNF, 10ng/ml) for 16 hours, at which time the amount of alkaline phosphataseproduced is measured by a standard colourimetric assay. Dose responsecurves were constructed from which EC₅₀ values were estimated.

In this test the compound of formula (I) showed an EC₅₀value of <1 nM.

The glucocorticoid receptor (GR) can function in at least two distinctmechanisms, by upregulating gene expression through the direct bindingof GR to specific sequences in gene promotors, and by downregulatinggene expression that is being driven by other transcription factors(such as NFκB or AP-1) through their direct interaction with GR.

In a variant of the above method, to monitor these functions, tworeporter plasmids have been generated and introduced separately intoA549 human lung epithelial cells by transfection. The first cell linecontains the firefly luciferase reporter gene under the control of asynthetic promoter that specifically responds to activation of thetranscription factor NFκB when stimulated with TNFα. The second cellline contains the renilla luciferase reporter gene under the control ofa synthetic promotor that comprises 3 copies of the consensusglucocorticoid response element, and which responds to directstimulation by glucocorticoids. Simultaneous measurement oftransactivation and transrepression was conducted by mixing the two celllines in a 1:1 ratio in 96 well plate (40,000 cells per well) andgrowing overnight at 37° C. Test compounds were dissolved in DMSO, andadded to the cells at a final DMSO concentration of 0.7%. Afterincubation for 1 h 0.5 ng/ml TNFα (R&D Systems) was added and after afurther 15 hours at 37° C., the levels of firefly and renilla luciferasewere measured using the Packard Firelite kit following themanufacturers' directions. Dose response curves were constructed fromwhich EC₅₀ values were determined. Transactivation (GR) Transrepression(NFκB) ED₅₀ (nM) ED₅₀ (nM) Compound of Formula (I) 0.06 0.20 Metabolite(X) >250 >1000 Fluticasone propionate 0.07 0.16In Vivo Pharmacological Activity

Pharmacological activity in vivo was assessed in an ovalbumin sensitisedBrown Norway rat eosinophilia model. This model is designed to mimicallergen induced lung eosinophilia, a major component of lunginflammation in asthma.

For the experiments in this section, compound of formula (I) was used asunsolvated Form 1.

Compound of formula (I) produced dose dependant inhibition of lungeosinophilia in this model after dosing as an intra-tracheal (IT)suspension in saline 30 min prior to ovalbumin challenge. Significantinhibition is achieved after a single dose of 30 μg of compound offormula (I) and the response was significantly (p=0.016) greater thanthat seen with an equivalent dose of fluticasone propionate in the samestudy (69% inhibition with compound of formula (I) vs 41% inhibitionwith fluticasone propionate).

In a rat model of thymus involution 3 daily IT doses of 100 μg ofcompound (I) induced significantly smaller reductions in thymus weight(p=0.004) than an equivalent dose of fluticasone propionate in the samestudy (67% reduction of thymus weight with compound (I) vs 78% reductionwith fluticasone propionate).

Taken together these results indicate a superior therapeutic index forcompound (I) compared to fluticasone propionate.

In Vitro Metabolism in Rat and Human Hepatocytes

Incubation of compound (I) with rat or human hepatocytes shows thecompound to be metabolised in an identical manner to fluticasonepropionate with the 17-β carboxylic acid (X) being the only significantmetabolite produced. Investigation of the rate of appearance of thismetabolite on incubation of compound (1) with human hepatocytes (37° C.10 μM drug concentration, hepatocytes from 3 subjects, 0.2 and 0.7million cells/mL) shows compound (I) to be metabolised ca. 5-fold morerapidly than fluticasone propionate:— 17-β acid metabolite productionSubject Cell density (pmol/h) number (million cells/mL) Compound (I)Fluticasone propionate 1 0.2 48.9 18.8 1 0.7 73.3 35.4 2 0.2 118 9.7 20.7 903 23.7 3 0.2 102 6.6 3 0.7 580 23.9

Median metabolite production 102-118 pmol/h for compound (I) and18.8-23.0 pmol/h for fluticasone propionate.

Pharmacokinetics after Intravenous (IV) and Oral Dosing in Rats

Compound (I) was dosed orally (0.1 mg/kg) and IV (0.1 mg/kg) to maleWistar Han rats and pharmacokinetic parameters determined. Compound (I)showed negligible oral bioavailability (0.9%) and plasma clearance of47.3 mL/min/kg, approaching liver blood flow (plasma clearance offluticasone propionate=45.2 mL/min/kg).

Pharmacokinetics after intra-tracheal Dry Powder Dosing in the Pig.

Anaesthetised pigs (2) were dosed intra-tracheally with a homogenousmixture of compound (I) (1 mg) and fluticasone propionate (1 mg) as adry powder blend in lactose (10% w/w). Serial blood samples were takenfor up to 8 h following dosing. Plasma levels of compound (I) andfluticasone propionate were determined following extraction and analysisusing LC-MS/MS methodology, the lower limits of quantitation of themethods were 10 and 20 pg/mL for compound (I) and fluticasone propionaterespectively. Using these methods compound (I) was quantifiable up to 2hours after dosing and fluticasone propionate was quantifiable up to 8hours after dosing. Maximum plasma concentrations were observed for bothcompounds within 15 min after dosing. Plasma half-life data obtainedfrom IV dosing (0.1 mg/kg) was used to calculate AUC (0-inf) values forcompound (I). This compensates for the plasma profile of Compound (I)only being defined up to 2 hours after an IT dose and removes any biasdue to limited data between compound (I) and fluticasone propionate.

C_(max) and AUC (0-inf) values show markedly reduced systemic exposureto compound (I) compared to fluticasone propionate:— Cmax (pg/mL) AUC(0-inf) (hr · pg/mL) Pig 1 Pig 2 Pig 1 Pig 2 Compound of Formula (I) 117 81 254 221 Fluticasone propionate 277 218 455 495

The pharmacokinetic parameters for both compound (I) and fluticasonepropionate were the same in the anaesthetised pig following intravenousadministration of a mixture of the two compounds at 0.1 mg/kg. Theclearance of these two glucocorticoids is similar is this experimentalpig model.

Example 1 Dry Powder Composition Containing 6α,9α-Difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydrox-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicAcid S-fluoromethyl Ester, Unsolvated Form 1, and a Long ActingMuscarinic Receptor Antagonist

A dry powder formulation may be prepared as follows:6α,9α-Difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy- 0.20 mg16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethylester, unsolvated Form 1 (prepared according to Intermediate 2 andmicronised to a MMD of 3 μm): Tiotropium bromide (micronised to a MMD of3 μm): 0.01 mg milled lactose (wherein not greater than 85% of particles  12 mg have a MMD of 60-90 μm, and not less than 15% of particles havea MMD of less than 15 μm):

A peelable blister strip containing 60 blisters each filled with aformulation as just described may be prepared.

Example 2 Aerosol Formulation Containing 6α,9α-Difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicAcid S-fluoromethyl Ester, Unsolvated Form 1, and a Long ActingMuscarinic Receptor Antagonist

An aluminium canister may be filled with a formulation as follows:6α,9α-Difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy- 250 μg16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethylester, Unsolvated Form 1 (prepared according to Intermediate 2) andmicronised to a MMD of 3 μm): Tiotropium bromide (micronised to a MMD of3 μm): 20 μg 1,1,1,2-tetrafluoroethane: to 50 μl(amounts per actuation)in a total amount suitable for 120 actuations and the canister may befitted with a metering valve adapted to dispense 50 μl per actuation.

Inhalers of the invention will now be described, by way of example only,with reference to, and as shown in, the accompanying drawings in which:

FIGS. 1 to 4 relate to a dry powder inhalers;

FIG. 5 relates to a metered dose inhaler;

FIG. 6 relates to a nasal inhaler.

FIG. 1 shows a suitable medicament carrier in the form of a capsule.

FIG. 2 a is a cross-sectional side elevation of a suitable elongatemedicament blister strip.

FIG. 2 b is a top perspective of the medicament blister stripillustrated in FIG. 2 a.

FIG. 3 shows a cross-sectional dry powder inhaler (DPI) comprising apowder reservoir.

FIG. 4 shows a cross-sectional dry powder inhaler (DPI) comprising anelongate medicament blister strip.

The medicament carrier in FIG. 1 is in the form of a capsule 1comprising a wall 2 enclosing medicament powder 5. Medicament powder 5is released on piercing the wall 2 of capsule 1 and may be inhaled by apatient.

FIG. 2 a shows a sectional side-elevation of a single blister strip 106comprising a pocket 107, containing dry powder 105, base 110 and lidcomprising laminates 114, 115. The lid is composed of a metallic foillaminate 114 bound to a plastic laminate 115. In the diagram, the lid114, 115 is hermetically sealed to base 110 by appropriate means (e.g.adhesion, welding). Base 110 comprises an organic polymeric plastic 103.A top perspective view of the blister strip 106 showing pockets 107 isillustrated in FIG. 2 b. Laminated lid 114, 115 is sealed to base 110.

FIG. 3 shows a sectional view of a dry powder inhaler 420 for dispensingmedicament in accord with the present invention. The inhaler 420comprises a body 421 which defines a reservoir 423 and a reservoir cover424. The reservoir contains a supply of medicament in dry powder form405. The walls 423 of the reservoir, defined by the body 421, arecomprised of a plastic material 403. Base 425 and body 421 define anaperture 430 through which powder 405 can pass from the reservoir to thedosing member 432. Powder 405 is guided by the walls 423 of thereservoir, which form a hopper, to the dosing member 432. Extendinglaterally from the lower end of the main body 421 is mouthpiece 435,through which the patient inhales via passage 433. If the device wereintended for nasal inhalation this would be replaced by a nosepiece.

FIG. 4 shows a simplified cross-sectional plan view of a dry powderinhaler comprising an elongate medicament carrier suitable fordispensing medicament in accord with the present invention. The inhaler540 dispenses unit doses of medicament powder from a medicament blisterstrip 506. The inhaler is comprised of an outer casing 544 enclosing amedicament strip 506 within body 521. The medicament strip may be, forexample, any of those described in FIGS. 2 a to 2 b above. The patientuses the inhaler by holding the device to his mouth, depressing lever538, and inhaling through mouthpiece 535. Depression of lever 538activates the internal mechanism of the inhaler, such that the lid 514and base 510 sheets of coiled medicament blister strip 506 are separatedat index wheel 541 by use of contracting wheel 542 and base wheel 543. Aunit dose of powdered medicament within blister pocket 507 is releasedand may be inhaled by the patient through exit port 533 and mouthpiece535.

FIG. 5 is a schematic representation of a section through a standardmetered dose inhalation device.

The standard metered dose inhaler shown in FIG. 1 comprises a housing 10in which an aerosol canister 20 can be located. The housing is open atone end (which will hereinafter be considered to be the top of thedevice for convenience of description) and is closed at the other. Anoutlet 30 leads laterally from the closed end of the housing 10. In theembodiment illustrated, the outlet 30 is in the form of a mouthpieceintended for insertion into the mouth of the patient but it may, ifdesired, be designed as a nozzle for insertion into the patient'snostril.

The aerosol canister 20, comprising a neck region 21 and ferrule 22, hasan outlet valve stem 40 at one end. This valve member can be depressedto release a measured dose from the aerosol canister or, alternatively,the valve stem 40 can be fixed and the main body of the canister can bemoved relative to the valve member to release the dose.

As shown in FIG. 5, the aerosol canister 20 is located in the housing 10so that one end protrudes from its open top, the canister beingpositioned such that the neck 21 and valve ferrule 22 are enclosedwithin housing 10. Spacer ribs (not shown) may be provided inside thehousing to hold the external surface of the canister 20 spaced from theinternal surface of the housing 10. A support 50 is provided at thelower end of the housing 10 and has a passage 60 in which the valve stem40 of the aerosol canister 20 can be located and supported. A secondpassage 70 is provided in the support 50 and is directed towards theinterior of the outlet 30. Thus, when the parts are in the positionsshown in FIG. 1, the protruding portion of the aerosol canister 20 canbe depressed to move the canister relative to the valve stem 40 to openthe valve and a dose of medicament contained in the aerosol will bedischarged through the passage 70 and into the outlet 30 from which itcan be inhaled by a patient. One dose will be released from the aerosolcanister each time it is fully depressed.

FIG. 6 shows an exploded view of a nasal inhaler suitable for use inaccord with the invention;

With reference to FIG. 6 there is shown a nasal inhaler device 5comprising a body 6 a container 3 and a nasal pump 8. The device furthercomprises a protective end cap 7 having an inner surface 4 forengagement with the body 6 to protect the dispensing nozzle 11.

The body 6 is made from a plastic material and defines a housing 9 and adispensing nozzle 11. The housing 9 defines a cavity formed by a sidewall and a first end wall and a second end wall 14. The dispensingnozzle 11 is connected to and extends away from the second end wall 14and has an external tapering form.

The dispensing nozzle 11 has a longitudinally extending orifice definedby an outlet tube extending towards the cavity 10. An annular abutmentis formed within the orifice part way along the outlet tube. The annularabutment defines a small aperture through which fluid can flow in use.

The nasal pump 8 comprises a hollow casing 30 defining a reservoircontaining several doses of the fluid nasal formulation to be dispensedand a plunger slidably engaged within the hollow casing 30. One detailedexample of a suitable nasal pump is described in U.S. Pat. No. 4,964,069incorporated herein by reference.

Throughout the specification and the claims which follow, unless thecontext requires otherwise, the word ‘comprise’, and variations such as‘comprises’ and ‘comprising’, will be understood to imply the inclusionof a stated integer or step or group of integers but not to theexclusion of any other integer or step or group of integers or steps.

The patents and patent applications described in this application areherein incorporated by reference.

1. A pharmaceutical composition comprising a compound of formula (I),

or a solvate thereof, in combination with a muscarinic receptorantagonist.
 2. A pharmaceutical composition according to claim 1 whereinthe muscarinic receptor antagonist is selective for the M1 and M3receptors over the M2 receptor.
 3. A pharmaceutical compositionaccording to claim 1 wherein the muscarinic receptor antagonist isipratropium or a salt thereof or oxitropium or a salt thereof.
 4. Apharmaceutical composition according to claim 1 wherein the muscarinicreceptor antagonist is long acting.
 5. A pharmaceutical compositionaccording to claim 4 wherein the muscarinic receptor antagonist istiotropium or a salt thereof.
 6. A pharmaceutical composition accordingto claim 1 wherein the muscarinic receptor antagonist is a compound offormula (A):

wherein: © is a phenyl ring, a C₄ to C₉ heteroaromatic group containingone or more heteroatoms (preferably selected from nitrogen, oxygen andsulphur atoms), or a naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl orbiphenyl group; R¹, R² and R³ each independently represent a hydrogen orhalogen atom, or a hydroxy group, or a phenyl, —OR⁴, —SR⁴, —NR⁴R⁵,—NHCOR⁴, —CONR⁴R, —CN, —NO₂, —COOR⁴ or —CF₃ group, or a straight orbranched lower alkyl group which may optionally be substituted, forexample, with a hydroxy or alkoxy group, wherein R⁴ and R⁵ eachindependently represent a hydrogen atom, straight or branched loweralkyl group, or together form an alicyclic ring; or R¹ and R² togetherform an aromatic, alicyclic or heterocyclic ring; n is an integer from 0to 4; A represents a —CH₂—, —CH═CR⁶—, —CR⁶═CH—, —CR⁶R⁷—, —CO—, —O—, —S—,—S(O)—, SO₂ or —NR⁶— group, wherein R⁶ and R⁷ each independentlyrepresent a hydrogen atom, straight or branched lower alkyl group, or R⁶and R⁷ together form an alicyclic ring; m is an integer from 0 to 8;provided that when m=0, A is not —CH₂—; p is an integer from 1 to 2 andthe substitution in the azoniabicyclic ring may be in the 2, 3 or 4position including all possible configurations of the asymmetriccarbons; B represents a group of formula (i) or (ii):

wherein R¹⁰ represents a hydrogen atom, a hydroxy or methyl group; andR⁸ and R⁹ each independently represents one of the following 5 moieties:

wherein R¹¹ represents a hydrogen or halogen atom, or a straight orbranched lower alkyl group and Q represents a single bond, —CH₂—,—CH₂—CH₂—, —O—, —O—CH₂—, —S—, —S—CH₂— or —CH═CH—, and when (i) or (i)contain a chiral centre they may represent either configuration; Xrepresent a pharmaceutically acceptable anion of a mono or polyvalentacid.
 7. A pharmaceutical composition according to claim 6 wherein where© represents a phenyl, pyrrolyl, or thienyl group; R¹, R² and R³ eachindependently represent a hydrogen atom, a hydroxy group or a halogenatom; n=0 or 1; m is an integer 1, 2 or 3; A represents a —CH₂—, —CH═CH—or —O— group; p=2 and the substituent group —OC(O)B attached to theazoniabicyclo[2.2.2]octane is at the 3 position having the (R)configuration; the —OC(O)B group is diphenylacetoxy,2-hydroxy-2,2-diphenyl-acetoxy, 2,2-diphenylpropionyloxy,2-hydroxy-2-phenyl-2-thien-2-yl-acetoxy,2-furan-2-yl-2-hydroxy-2-phenylacetoxy, 2,2-dithien-2-ylacetoxy,2-hydroxy-2,2-di-thien-2-ylacetoxy, 2-hydroxy-2,2-di-thien-3-ylacetoxy,9-hydroxy-9 [H]-fluorene-9-carbonyloxy,9-methyl-9[H]-fluorene-9-carbonyloxy, 9[H]-xanthene-9-carbonyloxy,9-hydroxy-9 [H]-xanthene-9-carbonyloxy or9-methyl-9[H]-xanthene-9-carbonyloxy; and the azoniabicyclo group issubstituted on the nitrogen atom with a 3-phenoxypropyl,2-phenoxypropyl, 3-phenylallyl, phenethyl, 4-phenylbutyl,3-phenylpropyl, 3-[2-hydroxyphenoxy]propyl, 3-[4-flurophenoxy]propyl,2-benzyloxyethyl, 3-pyrrol-1-ylpropyl, 2-thien-2-ylethyl or3-thien-2-ylpropyl group.
 8. A pharmaceutical composition according toclaim 1 wherein the compound of formula (I) or a solvate thereof and themuscarinic receptor antagonist are both present in particulate form. 9.A pharmaceutical composition according to claim 8 further comprising aparticulate carrier.
 10. A pharmaceutical composition according to claim9 wherein the carrier is lactose.
 11. A pharmaceutical compositionaccording to claim 1 further comprising a liquified propellant gas. 12.A pharmaceutical composition according to claim 1 wherein the compoundof formula (I) is in unsolvated form.
 13. A pharmceutical compositionaccording to claim 12 wherein the compound of formula (I) is inunsolvated form as polymorph Form
 1. 14. A pharmceutical compositionaccording to claim 1 further comprising a long-acting β₂-adrenoreceptoragonist.
 15. A pharmaceutical composition according to claim 1 adaptedfor administration by inhalation.
 16. A pharmaceutical compositionaccording to claim 15 for use in the treatment of inflammatory andallergic disorders of the respiratory tract.
 17. A method of treatmentof a inflammatory disorder of the respiratory tract which comprisesadministration by inhalation of a pharmaceutical composition accordingto claim
 1. 18. A method of treatment according to claim 17 wherein theinflammatory disorder of the respiratory tract is COPD or asthma.
 19. Aformulation according to claim 1 for use in human or veterinary medicinein the treatment of patients with inflammatory and/or allergic conditionfor treatment once-per-day.
 20. The use of a formulation as according toclaim 1 for the manufacture of a medicament for the treatment of apatient with an inflammatory and/or allergic condition
 21. An inhalercontaining a plurality of doses of a pharmaceutical formulationcomprising a compound of formula (I)

or a solvate thereof, in combination with a long-acting muscarinicreceptor antagonist, which formulation has a therapeutically usefuleffect in the treatment of inflammatory disorders of the respiratorytract over a period of 24 hours or more, and which doses are suitablefor once-per-day administration of the formulation by inhalation.
 22. Aninhaler according to claim 19 wherein the compound of formula (I) or asolvate thereof and the long-acting muscarinic receptor antagonist areboth present in particulate form.
 23. An inhaler according to claim 20wherein the formulation further comprises a particulate carrier.
 24. Aninhaler according to claim 21 wherein the carrier is lactose.
 25. Aninhaler according to claim 19 wherein the formulation further comprisesa liquefied propellant gas.
 26. An inhaler containing a plurality ofdoses of a pharmaceutical formulation comprising a particulate compoundof formula (I)

or a solvate thereof, a particulate long-acting muscarinic receptorantagonist and a carrier, each drug being present in an amount adequateto provide a therapeutically useful effect in the treatment ofinflammatory disorders of the respiratory tract over a period of 24hours or more following once-per-day dosing by inhalation.
 27. Aninhaler according to claim 19 wherein the inflammatory disorder of therespiratory tract is asthma or COPD.